2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors

ABSTRACT

Compounds of formula (I): 
                         
or pharmaceutically acceptable salts or solvates thereof, and their use as pharmaceuticals, particularly as p38 kinase inhibitors.

This application is filed Dursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/EP02/11575 filed Oct. 16, 2002, which claims Drioritv from GB0124938.2 filed Oct. 17, 2001.

This invention relates to novel compounds and their use aspharmaceuticals, particularly as p38 kinase inhibitors, for thetreatment of certain diseases and conditions.

We have now found a group of novel compounds that are inhibitors of p38kinase.

According to the invention there is provided a compound of formula (I):

wherein

when m is 0 to 4 R¹ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl,C₂₋₆alkenyl, —SO₂NR⁴R⁵, —CONR⁴R⁵ and —COOR⁴;

and when m is 2 to 4 R¹ is additionally selected from C₁₋₆alkoxy,hydroxy, NR⁴R⁵, —NR⁴SO₂R⁵, —NR⁴SOR⁵, —NR⁴COR⁵, and —NR⁴CONR⁴R⁵;

R² is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(n)—C₃₋₇cycloalkyl;

R³ is the group

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₆alkyl,heterocyclyl optionally substituted by C₁₋₄alkyl; and phenyl wherein thephenyl is optionally substituted by up to two groups independentlyselected from C₁₋₆alkoxy, C₁₋₆alkyl and halogen; or R⁴ and R⁵, togetherwith the nitrogen atom to which they are bound, form a five- tosix-membered heterocyclic or heteroaryl ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and nitrogen, whereinthe ring may be substituted by up to two C₁₋₆alkyl groups;

R⁶ is selected from hydrogen and C₁₋₄alkyl;

U is selected from methyl and halogen;

X and Y are each selected independently from hydrogen, methyl andhalogen;

m is selected from 0, 1, 2, 3 and 4 wherein each carbon atom of theresulting carbon chain may be optionally substituted with one or twogroups selected independently from C₁₋₆alkyl;

n is selected from 0, 1, 2 and 3;

r is selected from 0, 1 and 2;

or a pharmaceutically acceptable salt or solvate thereof.

According to a further embodiment of the invention there is provided acompound of formula (IA):

wherein R¹, R², R³ and m are as defined above, or a pharmaceuticallyacceptable salt or solvate thereof.

In a preferred embodiment, the molecular weight of a compound of formula(I) does not exceed 1000, more preferably 800, even more preferably 600.

In a preferred embodiment, R¹ is selected from C₁₋₄alkyl, in particular,methyl, or iso-propyl, C₃₋₆cycloalkyl, in particular cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, —CONHCH₃, —SO₂NH₂, —SO₂N(CH₃)₂,methoxy, —NHSO₂CH₃ and —NHCOCH₃. In a further preferred embodiment, R¹is selected from C₁₋₆alkyl, in particular 1,2-dimethylpropyl, isobutyl,1-methylbutyl, 2-methylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl andn-pentyl; C₃₋₇cycloalkyl, in particular cyclopropyl, cyclobutyl orcyclohexyl; C₂₋₆alkenyl, in particular 2-methylallyl; —CONR⁴R⁵, inparticular —CONHCH₃ or where R⁴ and R⁵ are independently selected fromhydrogen, C₁₋₆alkyl and phenyl optionally substituted by up to twogroups independently selected from C₁₋₆alkoxy; hydroxy; and NR⁴R⁵, inparticular where R⁴ and R⁵ are independently selected from hydrogen andC₁₋₆alkyl.

In a preferred embodiment, R² is selected from hydrogen, C₁₋₄alkyl and—CH₂-cyclopropyl, more preferably hydrogen.

In a preferred embodiment, R⁴ and R⁵ are independently selected fromhydrogen, C₁₋₄alkyl and phenyl. Particularly preferred are hydrogen andmethyl. Further particularly preferred groups are hydrogen, ethyl andphenyl optionally substituted by up to two groups independently selectedfrom C₁₋₆alkoxy.

In a preferred embodiment, R⁶ is selected from C₁₋₄alkyl, morepreferably methyl.

In a preferred embodiment, X and Y are each selected independently fromhydrogen, chlorine and fluorine. In a further preferred embodiment, X isfluorine.

In a preferred embodiment, m is selected from 0, 1 and 2, and when thecarbon chain of m is substituted, these substituents are preferably oneor two methyls. A further preferred substituent for m is t-butyl.

In a preferred embodiment, r is selected from 0 and 1. In particular, ris 0.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable salts andsolvates. Specific examples which may be mentioned include:

N-(Cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;

N-(3,3-Dimethylbutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;and

N-(2,3-Dimethylcyclohexyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl and t-butyl. A C₁₋₄alkyl group ispreferred, for example methyl, ethyl, isopropyl or t-butyl. The saidalkyl groups may be optionally substituted with one or more fluorineatoms, for example, trifluoromethyl.

As used herein, the term “alkoxy” refers to a straight or branched chainalkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy, 2-methylprop-1-oxy, 2-methyl prop-2-oxy, pentoxy, orhexyloxy. A C₁₋₄alkoxy group is preferred, for example methoxy orethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms whichmay optionally contain up to one double bond. For example,C₃₋₇cycloalkyl means a non-aromatic ring containing at least three, andat most seven, ring carbon atoms. Examples of “cycloalkyl” as usedherein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₃₋₆ cycloalkyl group ispreferred, for example, cyclopropyl, cyclopentyl or cyclohexyl. When R¹is a C₃₋₇cycloalkyl group, the cycloalkyl group may be optionallysubstituted by one or more groups selected from C₁₋₆alkyl and phenyl.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C₂₋₆alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl andpropenyl.

As used herein, the terms “heteroaryl ring” and “heteroaryl” refer to amonocyclic five- to seven-membered unsaturated ring containing at leastone heteroatom selected from oxygen, nitrogen and sulfur. Preferably,the heteroaryl ring has five or six ring atoms. Examples of heteroarylrings include, but are not limited to, furyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl. The said ring may be optionallysubstituted by one or more substituents independently selected fromC₁₋₆alkyl and oxy.

As used herein, the term “heterocyclic ring” and “heterocyclyl” refer toa monocyclic three- to seven-membered saturated or non-aromatic,unsaturated hydrocarbon ring containing at least one heteroatomindependently selected from oxygen, nitrogen and sulfur. Preferably, theheterocyclyl ring has five or six ring atoms. Examples of heterocyclylgroups include, but are not limited to, aziridinyl, pyrrolinyl,pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,piperidyl, piperazinyl, morpholino, and thiomorpholino. The said ringmay be optionally substituted by one or more substituents independentlyselected from C₁₋₆alkyl and oxy.

As used herein, the term “fused bicyclic ring” refers to a ring systemcomprising two five- to seven-membered saturated or unsaturatedhydrocarbon rings, the ring system containing at least one heteroatomindependently selected from oxygen, nitrogen and sulfur. Examples ofsuitable fused bicyclic rings include, but are not limited to, naphthyl,indolyl, indolinyl, benzothienyl, quinolyl, isoquinolyl,tetrahydroquinolyl, benzodioxanyl, indanyl and tetrahydronaphthyl. Eachring may be optionally substituted with one or more substituentsselected from halogen, C_(1.6)alkyl, oxy, —(CH₂)_(p)NR¹⁰R¹¹,—CO(CH₂)_(p)NR¹⁰R¹¹, and imidazolyl; and p is selected from 0 and 1.Particularly preferred substituents are chlorine, imidazolyl and—CH₂—N(CH₃)₂.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include water, ethanol and aceticacid. Most preferably the solvent used is water.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

Salts of the compounds of the present invention are also encompassedwithin the scope of the invention and may, for example, comprise acidaddition salts resulting from reaction of an acid with a nitrogen atompresent in a compound of formula (I).

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention.Representative salts include the following salts: Acetate,Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate,Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate,Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate,Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate,Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride,Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate,Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide, Trimethylammonium and Valerate. Other salts which are notpharmaceutically acceptable may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

For example, a general method (A) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 1 below.

-   (i) t-butyl carbazate, HOBT, HBTU, DIPEA, DMF-   (ii) TFA-   (iii) R⁴C(OEt)₃-   (iv) (4-Methoxycarbonylphenyl)boronic acid, (Ph₃P)₄Pd, CsCO₃, DME-   (v) LiOH, THF, H₂O-   (vi) R¹(CH₂)_(m)N R²H, HOBT, HBTU, DIPEA, DMF

For example, a general method (B) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 2 below.

-   (i) t-butyl carbazate, HOBT, HBTU, DIPEA, DMF-   (ii) TFA-   (iii) R⁴C(OEt)₃-   (iv) Bis(pinacolato)diboron, KOAc, PdCl₂dppf, DMF-   (v) SOCl₂-   (vi) R¹(CH₂)_(m)X(CH₂)_(n)N R²H, Na₂CO₃, acetone-   (vii) (Ph₃P)₄Pd, Na₂CO₃, DMF

For example, a general method (C) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 3 below.

-   (i) LiOH, THF, H₂O-   (ii) R¹(CH₂)_(m)NH₂, HOBT, HBTU, DIPEA, DMF-   (iii) R²-hal, NaH, DMF

Thus, according to the invention there is provided a process forpreparing a compound of formula (I) which comprises:

-   (a) reacting a compound of formula (XII)

wherein R³, U, X, Y and r are as defined above, with a compound offormula (XIII)R¹(CH₂)_(m)NR²H  (XIII)wherein R¹, R² and m are as defined above, under amide formingconditions;

-   b) reacting a compound of formula (XIIV)

wherein R³, X and Y are as defined above, with a compound of formula(XV)

wherein R¹, R², U, m and r are as defined above and hal is halogen, inparticular bromine or iodine, in the presence of a catalyst, for exampletetrakis(triphenylphosphine)palladium; or

-   c) reacting a compound of formula (XVI)

wherein R³, U, X, Y and r are as defined above, with a compound offormula (XVII)R¹(CH₂)_(m)NH₂  (XVII)wherein R¹ and m are as defined above, under amide forming conditions,followed by reaction with a compound of formula (XVIII)R²-hal  (XIII)in which R² and hal are as defined above, in the presence of a base suchas sodium hydride.

Suitable amide forming conditions are well known in the art and includetreating a solution of the acid, in for example DMF, with an amine inthe presence of, for example, HOBT, HBTU and DIPEA.

Whilst it is possible for the compounds, salts or solvates of thepresent invention to be administered as the new chemical, the compoundsof formula (I) and their pharmaceutically acceptable salts and solvatesare conveniently administered in the form of pharmaceuticalcompositions. Thus, in another aspect of the invention, we provide apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, in admixture withone or more pharmaceutically acceptable carriers, diluents orexcipients.

The compounds of formula (I) and their pharmaceutically acceptable saltsand solvates may be formulated for administration in any suitablemanner. They may, for example, be formulated for topical administrationor administration by inhalation or, more preferably, for oral,transdermal or parenteral administration. The pharmaceutical compositionmay be in a form such that it can effect controlled release of thecompounds of formula (I) and their pharmaceutically acceptable salts andsolvates. A particularly preferred method of administration, andcorresponding formulation, is oral administration.

For oral administration, the pharmaceutical composition may take theform of, and be administered as, for example, tablets (includingsub-lingual tablets) and capsules (each including timed release andsustained release formulations), pills, powders, granules, elixirs,tinctures, emulsions, solutions, syrups or suspensions prepared byconventional means with acceptable excipients.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules can be made by preparing a powder mixture as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The compounds of the present invention can also be administered in theform of liposome emulsion delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula(I) in combination with a pharmaceutically acceptable carrier.

Likewise, the composition may also be administered in nasal, ophthalmic,otic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscular,inhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

For parenteral administration, the pharmaceutical composition may begiven as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative. Alternatively for parenteraladministration the active ingredient may be in powder form forreconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively the composition may be formulated for topical application,for example in the form of ointments, creams, lotions, eye ointments,eye drops, ear drops, mouthwash, impregnated dressings and sutures andaerosols, and may contain appropriate conventional additives, including,for example, preservatives, solvents to assist drug penetration, andemollients in ointments and creams. Such topical formulations may alsocontain compatible conventional carriers, for example cream or ointmentbases, and ethanol or oleyl alcohol for lotions. Such carriers mayconstitute from about 1% to about 98% by weight of the formulation; moreusually they will constitute up to about 80% by weight of theformulation.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

The pharmaceutical compositions generally are administered in an amounteffective for treatment or prophylaxis of a specific condition orconditions. Initial dosing in human is accompanied by clinicalmonitoring of symptoms, such symptoms for the selected condition. Ingeneral, the compositions are administered in an amount of active agentof at least about 100 μg/kg body weight In most cases they will beadministered in one or more doses in an amount not in excess of about 20mg/kg body weight per day. Preferably, in most cases, dose is from about100 μg/kg to about 5 mg/kg body weight, daily. For administrationparticularly to mammals, and particularly humans, it is expected thatthe daily dosage level of the active agent will be from 0.1 mg/kg to 10mg/kg and typically around 1 mg/kg. It will be appreciated that optimumdosage will be determined by standard methods for each treatmentmodality and indication, taking into account the indication, itsseverity, route of administration, complicating conditions and the like.The physician in any event will determine the actual dosage which willbe most suitable for an individual and will vary with the age, weightand response of the particular individual. The effectiveness of aselected actual dose can readily be determined, for example, bymeasuring clinical symptoms or standard ant-inflammatory indicia afteradministration of the selected dose. The above dosages are exemplary ofthe average case. There can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention. For conditions or disease states as are treated bythe present invention, maintaining consistent daily levels in a subjectover an extended period of time, e.g., in a maintenance regime, can beparticularly beneficial.

In another aspect, the present invention provides a compound of formula(I) or a salt or solvate thereof, for use in therapy.

The compounds of the present invention are generally inhibitors of theserine/threonine kinase p38 and are therefore also inhibitors ofcytokine production which is mediated by p38 kinase. Within the meaningof the term “inhibitors of the serine/threonine kinase p38” are includedthose compounds that interfere with the ability of p38 to transfer aphosphate group from ATP to a protein substrate according to the assaydescribed below.

It will be appreciated that the compounds of the invention may beselective for one or more of the isoforms of p38, for example p38α,p38β, p38γ and/or p38δ. In one embodiment, the compounds of theinvention selectively inhibit the p38α isoform. In another embodiment,the compounds of the invention selectively inhibit the p38β isoform. Ina further embodiment, the compounds of the invention selectively inhibitthe p38α and p38β isoforms. Assays for determining the selectivity ofcompounds for the p38 isoforms are described in, for example, WO99/61426, WO 00/171535 and WO 02/46158.

It is known that p38 kinase activity can be elevated (locally orthroughout the body), p38 kinase can be incorrectly temporally active orexpressed, p38 kinase can be expressed or active in an inappropriatelocation, p38 kinase can be constitutively expressed, or p38 kinaseexpression can be erratic; similarly, cytokine production mediated byp38 kinase activity can be occurring at inappropriate times,inappropriate locations, or it can occur at detrimentally high levels.

Accordingly, the present invention provides a method for the treatmentof a condition or disease state mediated by p38 kinase activity, ormediated by cytokines produced by the activity of p38 kinase, in asubject which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof. The compound may be administered asa single or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention also provides a method of inhibiting cytokineproduction which is mediated by p38 kinase activity in a subject, e.g. ahuman, which comprises administering to said subject in need of cytokineproduction inhibition a therapeutic, or cytokine-inhibiting, amount of acompound of the present invention. The compound may be administered as asingle or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention treats these conditions by providing atherapeutically effective amount of a compound of this invention. By“therapeutically effective amount” is meant a symptom-alleviating orsymptom-reducing amount, a cytokine-reducing amount, acytokine-inhibiting amount, a kinase-regulating amount and/or akinase-inhibiting amount of a compound. Such amounts can be readilydetermined by standard methods, such as by measuring cytokine levels orobserving alleviation of clinical symptoms. For example, the cliniciancan monitor accepted measurement scores for anti-inflammatorytreatments.

The compounds of the present invention can be administered to anysubject in need of inhibition or regulation of p38 kinase or in need ofinhibition or regulation of p38 mediated cytokine production. Inparticular, the compounds may be administered to mammals. Such mammalscan include, for example, horses, cows, sheep, pigs, mice, dogs, cats,primates such as chimpanzees, gorillas, rhesus monkeys, and, mostpreferably, humans.

Thus, the present invention provides methods of treating or reducingsymptoms in a human or animal subject suffering from, for example,rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema,allergic rhinitis, allergic conjunctivitis, adult respiratory distresssyndrome, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, silicosis, endotoxemia, toxic shocksyndrome, inflammatory bowel disease, tuberculosis, atherosclerosis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiplesclerosis, aneurism, stroke, irritable bowel syndrome, muscledegeneration, bone resorption diseases, osteoporosis, diabetes,reperfusion injury, graft vs. host reaction, allograft rejections,sepsis, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to aquired immune deficiency syndrome(AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lymedisease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, cancer including breast cancer, colon cancer, lung canceror prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy and cancer including breast cancer, coloncancer, lung cancer and prostatic cancer, which comprises administeringto said subject a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease and cancer including breast cancer, colon cancer, lungcancer and prostatic cancer, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease andepilepsy which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from any type of pain includingchronic pain, rapid onset of analgesis, neuromuscular pain, headache,cancer pain, acute and chronic inflammatory pain associated withosteoarthritis and rheumatoid arthritis, post operative inflammatorypain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia,post-hepatic neuralgia, inflammatory neuropathies and migraine painwhich comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state mediated by p38 kinase activity or mediated by cytokinesproduced by p38 kinase activity.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, osteoarthritis,asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis,adult respiratory distress syndrome, chronic pulmonary inflammation,chronic obstructive pulmonary disease, chronic heart failure, silicosis,endotoxemia, toxic shock syndrome, inflammatory bowel disease,tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritablebowel syndrome, muscle degeneration, bone resorption diseases,osteoporosis, diabetes, reperfusion injury, graft vs. host reaction,allograft rejections, sepsis, systemic cachexia, cachexia secondary toinfection or malignancy, cachexia secondary to aquired immune deficiencysyndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis,Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, and cancer including breast cancer, colon cancer, lungcancer or prostatic cancer.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, asthma, psoriasis,chronic pulmonary inflammation, chronic obstructive pulmonary disease,chronic heart failure, systemic cachexia, glomerulonephritis, Crohn'sdisease, neurodegenerative disease, Alzheimer's disease, Parkinson'sdisease, epilepsy, and cancer including breast cancer, colon cancer,lung cancer and prostatic cancer.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, asthma, psoriasis,chronic pulmonary inflammation, chronic obstructive pulmonary disease,chronic heart failure, systemic cachexia, glomerulonephritis, Crohn'sdisease and cancer including breast cancer, colon cancer, lung cancerand prostatic cancer.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, neurodegenerativedisease, Alzheimer's disease, Parkinson's disease and epilepsy.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of any type ofpain including chronic pain, rapid onset of analgesia, neuromuscularpain, headache, cancer pain, acute and chronic inflammatory painassociated with osteoarthritis and rheumatoid arthritis, post operativeinflammatory pain, neuropathic pain, diabetic neuropathy, trigeminalneuralgia, post-hepatic neuralgia, inflammatory neuropathies andmigraine pain.

The compounds of formula (I) and their salts, solvates andphysiologically functional salts and solvates may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in rheumatoid arthritistherapy, combination with other chemotherapeutic or antibody agents isenvisaged. Combination therapies according to the present invention thuscomprise the administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof and at least oneother pharmaceutically active agent The compound(s) of formula (I) orpharmaceutically acceptable salt(s) or solvate(s) thereof and the otherpharmaceutically active agent(s) may be administered together orseparately and, when administered separately, this may occur separatelyor sequentially in any order. The amounts of the compound(s) of formula(I) or pharmaceutically acceptable salt(s) or solvate(s) thereof and theother pharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. Examples of other pharmaceutically active agentswhich may be employed in combination with compounds of formula (I) andtheir salts and solvates for rheumatoid arthritis therapy include:immunosuppresants such as amtolmetin guacil, nizoribine and rimexolone;anti-TNFα agents such as etanercept, infliximab, diacerein; tyrosinekinase inhibitors such as leflunomide; kallikrein antagonists such assubreum; interleukin 11 agonists such as oprelvekin; interferon beta 1agonists; hyaluronic acid agonists such as NRD-101 (Aventis);interleukin 1 receptor antagonists such as anakinra; CD8 antagonistssuch as amiprilose hydrochloride; beta amyloid precursor proteinantagonists such as reumacon; matrix metalloprotease inhibitors such ascipemastat and other disease modifying anti-rheumatic drugs (DMARDs)such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine,auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

EXAMPLES

The following examples are illustrative embodiments of the invention,not limiting the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature.

LCMS was conducted on a column (3.3 cm×4.6 mm ID, 3 um ABZ+PLUS), at aFlow Rate of 3 ml/min, Injection Volume of 5 μl, at room temperature andUV Detection Range at 215 to 330 nm.

General Method A:

A suspension of the hydrazide (4.36 mmol) in triethylorthoacetate (20ml) was warmed at 100° C. for 2 h and then at 130° C. for 1.5 h. Theexcess triethylorthoacetate was removed under vacuum and the residuepartitioned between ethyl acetate (50 ml) and water (50 ml). The organicmaterial was washed with water (50 ml), brine (50 ml) and dried withmagnesium sulphate. The solution was reduced to dryness under vacuum andthe residue triturated with cyclohexane to give the oxadiazole.

General Method B:

The t-butoxycarbonylhydrazide (7.57 mmol) was added portionwise to asolution of trifluoroacetic acid at 0° C. Once addition was complete,the solution was stirred at 0° C. for 15 min and then at roomtemperature for 30 min. The solution was reduced to dryness under vacuumand the residue partitioned between ethyl acetate (100 ml) and sodiumcarbonate solution (2N, 100 ml). The aqueous fraction was extracted withethyl acetate (2×75 ml). The combined organic fractions were washed withbrine (100 ml), dried (magnesium sulphate) and evaporated to drynessunder vacuum to give the hydrazide.

General Method C:

N,N-Disopropylethylamine (69.75 mmol) was added dropwise to a solutionof benzoic acid (23.25 mmol), HOBT (23.25 mmol), t-butylcarbazate (23.25mmol), HBTU (27.9 mmol) in DMF (15 ml) at 0° C. The reaction was stirredat 0° C. for 15 min and then at room temperature for 6 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (150 ml)and water (150 ml). The aqueous fraction was extracted with DCM (2×100ml). The combined organic fractions were washed with brine (100 ml),dried (magnesium sulphate) and evaporated to dryness under vacuum. Thesolid residue was washed with aqueous sodium carbonate (2N) and dried.

General Method D:

The aromatic bromide or iodide (4.0 mmol), phenylboronic acid (4.8mmol), tetrakis(triphenylphosphine)palladium (100 mg) and caesiumcarbonate (2.4 g) in DME (30 ml) were heated at 90° C. under nitrogenfor 20 h. The cooled reaction was preabsorbed onto silica andchromatographed on a silica SPE (10 g) eluting with an ethylacetate/cyclohexane gradient (0–100% ethyl acetate). The combinedproduct fractions were evaporated to dryness under vacuum.

General Method E:

The methyl benzoate (1.0 mmol) was dissolved in THF (10 ml) and asolution of lithium hydroxide monohydrate (2.1 mmol) in water (10 ml)added. The reaction mixture was heated at 75° C. for 4 h. The THF wasevaporated under vacuum and the solution acidified with hydrochloricacid (2N). The precipitate formed was filtered off, washed with waterand dried under vacuum.

General Method F:

Benzoic acid (0.1 mmol), HOBT (0.1 mmol), PyBOP (0.1 mmol) and amine(1.2 mmol) were mixed in 1.75 ml of DMF and DIPEA (52 μl) added, thereaction was stirred at room temperature for 72 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM andaqueous sodium hydrogen carbonate solution. The organic fraction wasseparated and the solution evaporated to dryness under vacuum. Theresidue was chromatographed on a silica SPE eluting with aDCM/ethanol/ammonia gradient (500:8:1 to 40:8:1). The product fractionswere combined and evaporated to dryness. The residue wasrechromatographed on silica SPE eluting with an ethylacetate/cyclohexane gradient (1:8 to 1:1). Product fractions evaporatedto dryness under vacuum.

General Method G:

Benzoic acid (3.1 mmol), HATU (3.7 mmol), DIPEA (6.8 mmol), and amine(3.1 mmol) were mixed in DMF (30 ml) and heated for 18 h at 80° C. Thesolvent was evaporated from the cooled reaction under vacuum and theresidue dissolved in DCM. The DCM solution was washed with aqueoussodium hydroxide (2M), hydrochloric acid (2M) and brine. Dried withmagnesium sulphate and the solvent evaporated under vacuum. The residuewas chromatographed on silica eluting with DCM/ethanol/ammonia (500:8:1)and the solvent evaporated under vacuum from the product fractions.

General Method H:

Secondary amide (0.06 mmol), iodoalkane or bromoalkane (3 drops) andsodium hydride, (60% in mineral oil, 0.5 mmol) were stirred in DMF (5ml) for 18 h. The reaction was acidified with hydrochloric acid (2N) andextracted with DCM (2×10 ml). The DCM was evaporated from the combinedextracts under vacuum and the residue purified by SPE (silica, 1 g)eluting with ethylacetate. The ethyl acetate was evaporated under vacuumto give the tertiary amide.

General Method I:

Benzoic acid (0.1 mmol), HATU (0.1 mmol), DIPEA (0.3 mmol), and amine(0.12 mmol) were mixed in THF (5 ml) and heated for 16 h at roomtemperature. The solvent was evaporated under vacuum and the residuedissolved in DCM. The DCM solution was washed with aqueous sodiumcarbonate (2M), absorbed onto a silica SPE (5 g) and eluted with aDCM/ethanol,/ammonia gradient (500:8:1–15:8:1). The solvent wasevaporated under vacuum from the product fractions to give the amide.

Example 1N-(3-Hydroxypropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

-   a)    2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic    acid (59 mg, 0.2 mmol), 3-amino-1-propanol (15 mg, 0.2 mmol) and    1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.2    mmol) were suspended in dry DCM (7 ml) and stirred at room    temperature under nitrogen for 20 h. 3-Amino-1-propanol (45 mg, 0.6    mmol) was added and the reaction stirred at room temperature for    21 h. 1-Hydroxybenzotriazole (27 mg, 0.2 mmol) was added and the    reaction heated at 35° C. for 70 h. Water (10 ml) was added to the    cooled reaction, and the organic fraction separated. The organic    phase was absorbed onto a silica flash column and eluted with a    DCM/ethanol/ammonia gradient (300:8:1 to 150:8:1). Solvent was    evaporated from the product fractions under vacuum to give    N-(3-hydroxypropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide    (21 mg, 30%).

NMR; δH[²H₆]-DMSO 8.52, (1H, t), 7.94–7.88, (3H, m), 7.75, (1H, m), 7.55–7.49, (3H, m), 3.47, (2H, t), 3.33, (2H, m), 2.56, (3H, s), 2.30, (3H,s), 1.69, (2H, m). LCMS; retention time 2.68 min, MH⁺ 352.

-   b)    2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic    acid    2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic    acid was prepared from methyl    2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylate    using method E.

NMR; δH[²H₆]-DMSO 8.03, (2H, d), 7.90, (1H, dd), 7.75, (1H, d),7.57–7.52, (3H, m), 2.56, (3H, s), 2.30, (3H, s). LCMS; retention time3.14 min, MH⁺ 295.

-   c) Methyl    2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylate    Methyl    2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylate    was prepared from    2-(3-bromo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole and    (4-methoxycarbonylphenyl)boronic acid using method D.

NMR; δH CDCl₃ 8.12, (2H, d), 7.94, (1H, dd), 7.90, (1H, d), 7.43, (3H,m), 3.96, (3H, s), 2.61, (3H, s), 2.33, (3H, s). LCMS; retention time3.37 min, MH⁺ 309.

-   d) 2-(3-Bromo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole    2-(3-Bromo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole was prepared    from (3-bromo-4-methylbenzoyl)hydrazine using method A.

NMR; δH[²H₆]-DMSO 8.08, (1H, d), 7.86, (1H, dd), 7.56, (1H, d), 2.56,(3H, s), 2.41, (3H, s). LCMS; retention time 3.19 min, MH⁺ 254.

-   e) (3-Bromo-4-methylbenzoyl)hydrazine    (3-Bromo-4-methylbenzoyl)hydrazine was prepared from t-butyl    2-(3-bromo-4-methylbenzoyl)hydrazine-1-carboxylate using method B.

NMR; δH[²H₆]-DMSO 9.82, (1H, b), 8.00, (1H, d), 7.73, (1H, dd), 7.42,(1H, d), 4.49, (2H, b), 2.36, (3H, s). LCMS; retention time 2.47 min.

-   f) t-Butyl 2-(3-bromo-4-methylbenzoyl)hydrazine-1-carboxylate    t-Butyl 2-(3-bromo-4-methylbenzoyl)hydrazine-1-carboxylate was    prepared from 3-bromo-4-methylbenzoic acid using method C.

NMR; δH[²H₆]-DMSO 10.25, (1H, b), 8.94, (1H, b), 8.04, (1H, s), 7.76,(1H, d), 7.47, (1H, d), 2.39, (3H, s), 1.41, (9H,s). LCMS; retentiontime 3.24 min, MH⁺ 330.

Example 2N-(Cyclopropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (59 mg, 0.2 mmol), cyclopropylamine (11 mg, 0.2 mmol) and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.2 mmol)were suspended in dry DCM (7 ml) and stirred at room temperature undernitrogen for 20 h. Cyclopropylamine (33 mg, 0.6 mmol) was added and thereaction stirred at room temperature for 21 h. 1-Hydroxybenzotriazole(27 mg, 0.2 mmol) was added and the reaction heated at 35° C. for 70 h.Water (10 ml) was added to the cooled reaction, and the organic fractionseparated. The organic phase was absorbed onto a silica flash column andeluted with DCI/ethanol/ammonia (300:8:1). Solvent was evaporated fromthe product fractions under vacuum to giveN-(cyclopropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide(26 mg, 39%).

NMR; δH[²H₆]-DMSO 8.51, (1H, d), 7.92–7.88, (3H, m), 7.75, (1H, d),7.54, (1H, d), 7.48,(2H, d), 2.87, (1H, m), 2.56, (3H, s), 2.30, (3H,s), 0.71, (2H, m), 0.59, (2H, m). LCMS; retention time 2.89 min, MH⁺334.

Example 3N-[(Dimethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

DIPEA (76 μl, 0.6 mmol) was added to a solution of2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (59 mg, 0.2 mmol), 3-dimethylaminopropylamine (20 mg, 0.2 mmol),HBTU (91 mg, 0.24 mmol) and HOBT (27 mg, 0.2 mmol) in DMF (0.5 ml). Thereaction was stirred at room temperature for 16 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (5 ml)and water (5 ml). The organic phase was absorbed onto a silica flashcolumn and eluted with DCM/ethanol/ammonia (80:8:1). The productfractions were concentrated under vacuum to giveN-[(dimethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide(37 mg, 49%).

NMR; δH[²H₆]-DMSO 8.58, (1H, t), 7.93, (2H, d), 7.89, (1H, dd), 7.76,(1d), 7.54, (1H, d), 7.50, (2H, d), 3.30, (2H, m), 2.56, (3H, s), 2.31,(3H, s), 2.28, (2H, t), 2.14, (6H, s), 1.67, (2H, m). LCMS; retentiontime 2.25 min, MH⁺ 379.

Example 4N-(Cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

-   a) Cyclopropylmethylamine (78 mg, 1.10 mmol), and    2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl    chloride (115 mg, 0.368 mmol) were mixed in DCM (15 ml) and stirred    at room temperature for 17 h. The reaction was absorbed onto a    silica flash column and eluted with DCM/ethanol/ammonia (150:8:1).    The product fractions were concentrated under vacuum to give    N-(cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide    as a white foam (75 mg, 59%).

NMR; δH[²H₆]-DMSO 8.65, (1H, t), 7.95, (2H, d), 7.89, (1H, dd), 7.76,(1H, d), 7.55 –7.49, (3H, m), 3.17, (2H, t), 2.56, (3H, s), 2.31, (3H,s), 1.05, (1H, m), 0.43, (2H, m), 0.24, (2H, m). LCMS; retention times3.15 min, MH⁺348.

-   b)    2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl    chloride Oxalyl chloride (0.073 ml, 0.82 mmol) was added to a    suspension of    2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl    carboxylic acid (200 mg, 0.68 mmol), and DMF (2 drops) in DCM    (10 ml) at 0° C. The reaction was stirred at room temperature for    1.5 h and the solvents evaporated under vacuum to give    2′-methyl-5′-(5-methyl-1,3,4    oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl chloride as a white solid    (0.212 g, 100%).

NMR; δH[²H₆]-DMSO 8.03, (2H, d), 7.90, (1H, dd), 7.76, (1H, d),7.56–7.53, (3H, m), 2.56, (3H, s), 2.30, (3H, s).

Example 5N-[3-(Diethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

DIPEA (130 μl, 1.0 mmol) was added to a solution of2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (100 mg, 0.34 mmol), 3-diethylaminopropylamine (49 mg, 0.37 mmol),HBTU (155 mg, 0.41 mmol) and HOBT (46 mg, 0.34 mmol) in DMF (1.0 ml).The reaction was stirred at room temperature for 66 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (5 ml)and water (5 ml) The organic phase was absorbed onto a silica flashcolumn and eluted with DCM/ethanol/ammonia (100:8:1). The productfractions were concentrated under vacuum to giveN-[3-(diethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide(88 mg, 64%).

NMR; δH[²H₆]-DMSO 8.60, (1H, t), 7.92, (2H, d), 7.89, (1H, dd), 7.75,(1H, d), 7.54, (1H, d), 7.50, (2H, d), 3.30, (2H, m), 2.56, (3H, s),2.46–2.41, (6H, m), 2.30, (3H, s), 1.65, (2H, m), 0.94, (6H, t). LCMS;retention time 2.44 min, MH⁺ 407.

Example 6N-(Cyclopropylmethyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

N-(Cyclopropylmethyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamidewas prepared fromN-(cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamideand iodomethane using method H.

NMR; δH[²H₆]-DMSO 7.89, (1H, dd), 7.76, (1H, d), 7.54, (1H, d), 7.47,(4H, s), 3.14–3.01, (5H, m), 2.56, (3H, s), 2.32, (3H, s), 1.08–0.95,(1H, b), 0.47, (2H, b), 0,29, (1H, b), 0.06, (1H, b). LCMS; retentiontime 3.20 min, MH⁺ 362.

Example 7N-(3-Hydroxypropyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

N-(3-Hydroxypropyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamidewas prepared from2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid and N-(3-hydroxypropyl)-N-methylamine using method I.

NMR; δH[²H₆]-DMSO 7.89, (1H, d), 7.76, (1H, s), 7.54, (1H, d), 7.46,(4H, s), 4.51–4.42, (1H, m), 3.49, (2H, s), 3.32, (3H, s), 2.95, (2H,s), 2.56, (3H, s), 2.32, (3h, s), 1.75, (2H, m). LCMS; retention time2.74 min, MH⁺ 366.

Example 8N-Cyclohexyl-N-ethyl-2′-methyl-5′-(5-methyl-1,34-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

N-Cyclohexyl-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamidewas prepared from2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid and N-cyclohexyl-N-ethylamine using method I.

NMR; δH[²H₆]-DMSO 7.89, (1H, dd), 7.77, (1H, s), 7.54, (1H, d), 7.46,(2H, d), 7.41, (2H, d), 3.37, (2H, b), 3.22, (1H, b), 2.56, (3H, s),2.31, (3H, s), 1.81–0.89, (13H, b). LCMS; retention time 3.57 min, MH⁺404.

Example 9N-Dicyclopropylmethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

N-Dicyclopropylmethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamidewas prepared from2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid and dicyclopropylmethylamine using method I.

NMR; δH[²H₆]-DMSO 7.89, (1H, d), 7.77, (1H, d), 7.54, (1H, d), 7.46,(4H, m), 3.46, (2H, b), 3.22, (2H, b), 2.56, (3H, s), 2.32, (3H, s),1.16, (1H, b), 0.98, (1H, b), 0.47, (4H, b), 0.33, (2H, b), 0.04, (2H,b). LCMS; retention time 3.59 min, MH⁺ 402.

Example 102′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-pentyl-1,1′-biphenyl-4-carboxamide

2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-pentyl-1,1′-biphenyl-4-carboxamidewas prepared from2′-methyl-5′-(S-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid and methylpentylamine using method I.

NMR; δH[²H₆]-DMSO 7.89, (1H, dd), 7.76, (1H, d), 7.54, (1H, d), 7.47,(4H, s), 3.45, (1H, m), 3.23, (1H, m), 2.96–2.93, (3H, m), 2.56, (3H,s), 2.31, (3H, s), 1.59–1.51, (2H, m), 1.32, (2H, b), 1.08, (2H, b),0.90–0.77, (3H, m). LCMS; retention time 3.47 min, MH⁺378.

Example 11N-(Cyclopropylmethyl)-5′-(5-ethyl-1,3,4-oxadiazol-2-yl)-2′-methyl-1,1′-biphenyl-4-carboxamide

-   a)    N-(Cyclopropylmethyl)-5′-(hydrazinocarbonyl)-2′-methyl-1,1′-biphenyl-4-carboxamide    (20 mg, 0.06 mmol) and triethylorthopropionate (211 mg, 1.2 mmol)    were heated at 130° C. for 18 h. The excess triethylorthopropionate    was evaporated under vacuum, the residue applied to a silica SPE and    eluted with an ethyl acetate/cyclohexane gradient (1:8 to 1:0). The    solvent was evaporated to yield    N-(cyclopropylmethyl)-5′-(5-ethyl-1,3,4-oxadiazol-2-yl)-2′-methyl-1,1′-biphenyl-4-carboxamide    (16.9 mg, 78%).

LCMS; retention time 3.36 min, MH⁺ 362.

-   b)    N-(Cyclopropylmethyl)-5′-(hydrazinocarbonyl)-2′-methyl-1,1′-biphenyl-4-carboxamide

5′-[2-t-Butoxycarbonyl(hydrazinocarbonyl)]-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide(450 mg, 1.06 mmol) was dissolved in trifluoroacetic acid (4 ml) andstirred at room temperature for 3.5 h. The trifluoroacetic acid wasevaporated under vacuum and the residue was partitioned between DCM andaqueous sodium bicarbonate. The organic phase and any precipitateproduced were separated, washed with brine and concentrated under vacuumto giveN-(cyclopropylmethyl)-5′-(hydrazinocarbonyl)-2′-methyl-1,1′-biphenyl-4-carboxamideas a white solid (210 mg, 61%).

LCMS; retention time 2.79 min, MH⁺ 324.

-   c)    5′-[2-t-Butoxycarbonyl(hydrazinocarbonyl)]-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide

4-[N-(Cyclopropylmethyl)aminocarbonyl]phenylboronic acid (356 mg, 1.63mmol), t-butyl 2-(3-bromo-4-methylbenzoyl)hydrazine-1-carboxylate (537mg, 1.63 mmol), tetrakis(triphenylphosphine)palladium (190 mg, 0.16mmol) and aqueous sodium bicarbonate (1M, 2.5 ml) were heated in DME (5ml) at 80° C. 9 h. The solvents were evaporated under vacuum and theresidue purified on a silica flash column eluting withDCM/ethanol/ammonia (300:8:1) to give after evaporation of the solvent5′-[2-t-butoxycarbonyl(hydrazinocarbonyl)]-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamideas a yellow foam (460 mg, 67%).

LCMS; retention time 3.28 min, MH⁺ 424.

-   d) 4-[N-(Cyclopropylmethyl)aminocarbonyl]phenylboronic acid

(Cyclopropylmethyl)amine (470 mg, 6.0 mmol), 4-carboxyphenylboronic acid(1.0 g, 6.0 mmol), HOBT (810 mg, 6.0 mmol), HBTU (2.73 g, 7.2 mmol) andDIPEA (1.71 g, 7.2 mmol) were mixed in DMF (10 ml) and stirred at roomtemperature for 18 h. The DMF was evaporated under vacuum and theresidue partitioned between DCM and aqueous sodium bicarbonate. Theorganic phase was separated, washed with water and brine and dried(magnesium sulphate). The solvent was evaporated under vacuum and theresidue purified on a silica flash column eluting withDCM/ethanol/ammonia (15:8:1 then 10:10:1), to give after evaporation ofthe solvents 4-[N-(cyclopropylmethyl)aminocarbonyl]phenylboronic acid(300 mg, 23%).

NMR; δH[²H₆]-DMSO 8.54, (1H, t), 8.18, (2H, s), 7.83, (2H, d), 7.78,(2H, d), 3.15, (2H, m), 1.02, (1H, m), 0.42, (2H, m), 0.21, (2H, m).

Example 12N-(Cyclopropylmethyl)-2′-methyl-5′-(5-n-propyl-1,3,3-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

N-(Cyclopropylmethyl)-5′-(hydrazinocarbonyl)-2′-methyl-1,1′-biphenyl-4-carboxamide(20 mg, 0.06 mmol) and triethylorthobutarate (229 mg, 1.2 mmol) wereheated at 130° C. for 18 h. The excess triethylorthobutarate wasevaporated under vacuum, the residue applied to a silica SPE and elutedwith an ethyl acetate/cyclohexane gradient (1:8 to 1:0). The solvent wasevaporated to yieldN-(cyclopropylmethyl)-2′-methyl-5′-(5-n-propyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

NMR; δH[²H₆]-DMSO 8.64, (1H, t), 7.95, (2H, d), 7.90, (1H, dd), 7.76,(1H, d), 7.55, (1H, d), 7.50, (2H, d), 3.17, (2H, t), 2.89, (2H, t),2.31, (3H, s), 1.77, (2H, m), 1.08, (1H, m), 0.96, (3H, t), 0.43, (2H,m), 0.24, (2H, m). LCMS; retention time 3.47 min, MH⁺ 376.

Example 13N-[2-(3,4-Dimethoxyphenylamino)-2-oxoethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

N-[2-(3,4-Dimethoxyphenylamino)-2-oxoethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from2′-methyl-5′-(5-methyl-1,3,4 oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid and 2-amino-N-(3,4-dimethoxyphenyl)acetamide using method I.

NMR; δH[²H₆]-DMSO 9.93, (1H, s), 8.92, (1H, t), 8.01, (2H, d), 7.90,(1H, dd), 7.78, (1H, d), 7.56–7.53, (3H, m), 7.33, (1H, d), 7.10, (1H,dd), 6.89, (1H, d), 4.06, (2H, d), 3.71, (6H, m), 2.57, (3H, s), 2.32,(3H, s). LCMS; retention time 2.96 min, MH⁺ 487.

Example 14N-(3,3-Dimethylbutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 3,3-dimethylbutylamine (0.34 mmol) were mixed in DMF(0.7 ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(3,3-dimethylbutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.46 min, MH⁺ 378.

Example 15N-(2,3-Dimethylcyclohexyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 2,3-dimethylcyclohexylamine (0.34 mmol) were mixed inDMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMFwas evaporated under vacuum and the residue partitioned between DCM (0.4ml) and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(2,3-dimethylcyclohexyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.57 min, MH⁺ 404.

Example 16N-(Isobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 Mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and isobutylamine (0.34 mmol) were mixed in DMF (0.7 ml) andthe reaction left at room temperature for 18 h. The DMF was evaporatedunder vacuum and the residue partitioned between DCM (0.4 ml) and water(0.4 ml). The organic phase was washed with aqueous sodium hydroxide(0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue waspurified by mass directed HPLC to giveN-(isobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.21 min, MH⁺ 350.

Example 17N-[2,2-Dimethyl-1-(methylaminocarbonyl)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 2-amino-N,3,3-trimethylbutanamide (0.34 mmol) were mixedin DMF (0.7 ml) and the reaction left at room temperature for 18 h. TheDMF was evaporated under vacuum and the residue partitioned between DCM(0.4 ml) and water (0.4 ml). The organic phase was washed with aqueoussodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-[2,2-dimethyl-1-(methylaminocarbonyl)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.03 min, MH⁺ 421.

Example 182′-Methyl-N-(3-methylcyclohexyl)-5′-(6-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 3-methylcyclohexylamine (0.34 mmol) were mixed in DMF(0.7 ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to give2′-methyl-N-(3-methylcyclohexyl)-5′-(6-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.50 min, MH⁺ 390.

Example 19N-Cyclohexyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenylcarboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and cyclohexylamine (0.34 mmol) were mixed in DMF (0.7 ml)and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-cyclohexyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.38 min, MH⁺ 376.

Example 20N-Cyclopropyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-arboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and cyclopropylamine (0.34 mmol) were mixed in DMF (0.7 ml)and the reaction left at room temperature for 18 hours. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-cyclopropyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.25 min, MH⁺ 362.

Example 21(1,2-Dimethylpropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 1,2-dimethylpropylamine (0.34 mmol) were mixed in DMF(0.7 ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(1,2-dimethylpropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.31 min, MH⁺ 364.

Example 22N-(1,3-Dimethylpentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,1-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 1,3-dimethylpentylamine (0.34 mmol) were mixed in DMF(0.7 ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(1,3-dimethylpentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.58 min, MH⁺ 392.

Example 23N-(2-Cyclohexylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl 4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042mmol) and 2-cyclohexylethylamine (0.34 mmol) were mixed in DMF (0.7 ml)and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(2-cyclohexylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.69 min, MH⁺ 404.

Example 242′-Methyl-N-(2-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 2-methylbutylamine (0.34 mmol) were mixed in DMF (0.7ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to give2′-methyl-N-(2-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.33 min, MH⁺ 364.

Example 25N-(Cyclobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and cyclobutylamine (0.34 mmol) were mixed in DMF (0.7 ml)and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(cyclobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.15 min, MH⁺ 348.

Example 26N-(1-Cyclopropylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 1-cyclopropylethylamine (0.34 mmol) were mixed in DMF(0.7 ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(1-cyclopropylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.13 min, MH⁺ 362.

Example 27N-(2,4-Dimethyl-3-pentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 2,4-dimethyl-3-pentylamine (0.34 mmol) were mixed in DMF(0.7 ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to giveN-(2,4-dimethyl-3-pentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.48 min, MH⁺ 392.

Example 282′-Methyl-N-(1-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 1-methylbutylamine (0.34 mmol) were mixed in DMF (0.7ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to give2′-methyl-N-(1-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.33 min, MH⁺ 364.

Example 292′-Methyl-N-(2-methylallyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide

2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylicacid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg,0.042 mmol) and 2-methylallylamine (0.34 mmol) were mixed in DMF (0.7ml) and the reaction left at room temperature for 18 h. The DMF wasevaporated under vacuum and the residue partitioned between DCM (0.4 ml)and water (0.4 ml). The organic phase was washed with aqueous sodiumhydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. Theresidue was purified by mass directed HPLC to give2′-methyl-N-(2-methylallyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.

LCMS; retention time 3.13 min, MH⁺ 348.

Abbreviations

-   DCM Dichloromethane-   DIPEA N,N-Diisopropylethylamine-   DME Dimethoxyethane-   DMF Dimethylformamide-   DMSO Dimethylsulphoxide-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybenzotriazole hydrate-   PyBOP Benzotriazol-1-yl-oxy-tripyrrolidinophosphonium    hexafluorophosphate-   SPE Solid phase extraction-   THF Tetrahydrofuran.

The activity of the compounds of the invention as p38 inhibitors may bedemonstrated in the following assays:

p38 Kinase Assay

The peptide substrate used in the p38 assay wasbiotin-IPTSPITTTYFFFRRR-amide. The p38 and MEK6 proteins were purifiedto homogeneity from E. coli expression systems. The fusion proteins weretagged at the N-terminus with Glutathione-S-Transferase (GST). Themaximum activation was achieved by incubating 20 uL of a reactionmixture of 30 nM MEK6 protein and 120 nM p38 protein in the presence of1.5 uM peptide and 10 mM Mg(CH₃CO₂)₂ in 100 mM HEPES, pH 7.5, added to15 uL of a mixture of 1.5 uM ATP with 0.08 uCi [g-P]ATP, with or without15 uL of inhibitor in 6% DMSO. The controls were reactions in thepresence (negative controls) or absence (positive controls) of 50 mMEDTA. Reactions were allowed to proceed for 60 min at room temperatureand quenched with addition of 50 uL of 250 mM EDTA and mixed with 150 uLof Streptavidin SPA beads (Amersham) to 0.5 mg/reaction. The DynatechMicrofluor white U-bottom plates were sealed and the beads were allowedto settle overnight. The plates were counted in a Packard TopCount for60 seconds. IC₅₀ values were obtained by fitting raw data to %I=100*(1−(I−C2)/(C1−C2)), where I was CPM of background, C1 was positivecontrol, and C2 was negative control.

α P38 Fluorescence Polarisation Method

α P38 was prepared in house. SB4777790-R Ligand was diluted in HEPEScontaining MgCl₂, CHAPS, DTT and DMSO. This was added to blank wells ofa Black NUNC 384 well plate. α P38 was added to this ligand mixture thenadded to the remainder of the 384 well plate containing controls andcompounds. The plates were read on an LJL Analyst and FluorescenceAnisotropy used to calculate the compound inhibition.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process or use claims and may include, by way ofexample and without limitation, one or more of the following claims:

1. A compound of formula (I):

wherein when m is 0 to 4, R¹ is selected from C₁₋₆alkyl, C₃₋₇cycloalkyl,C₂₋₆alkenyl, —SO₂NR⁴R⁵, —CONR⁴R⁵ and —COOR⁴; and when m is 2 to 4, R¹ isadditionally selected from C₁₋₆alkoxy, hydroxy, NR⁴R⁵, —NR⁴SO₂R⁵,—NR⁴SOR⁵, —NR⁴COR⁵, and —NR⁴CONR⁴ R⁵; R² is selected from hydrogen,C₁₋₆alkyl and —(CH₂)_(n)—C₃₋₇cycloalkyl;

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₆alkyl,heterocyclyl optionally substituted by C₁₋₄alkyl; and phenyl wherein thephenyl is optionally substituted by up to two groups independentlyselected from C₁₋₆alkoxy, C₁₋₆alkyl and halogen; or R⁴ and R⁵, togetherwith the nitrogen atom to which they are bound, form a five- tosix-membered heterocyclic or heteroaryl ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and nitrogen, whereinthe ring may be substituted by up to two C₁₋₆alkyl groups; R⁶ isselected from hydrogen and C₁₋₄alkyl; U is selected from methyl andhalogen; X and Y are each selected independently from hydrogen, methyland halogen; m is selected from 0, 1, 2, 3 and 4 wherein each carbonatom of the resulting carbon chain may be optionally substituted withone or two groups selected independently from C₁₋₆alkyl; n is selectedfrom 0, 1, 2 and 3; r is selected from 0, 1 and 2; or a pharmaceuticallyacceptable salt or solvate thereof.
 2. A compound according to claim 1wherein R¹ is selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, —CONHCH₃,—SO₂NH₂, —SO₂N(CH₃)₂, methoxy, —NHSO₂CH₃ and —NHCOCH₃.
 3. A compoundaccording to claim 1 wherein R¹ is selected from C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl, —CONR⁴R⁵, hydroxy and NR⁴R⁵.
 4. A compoundaccording to claim 1 wherein R² is selected from hydrogen, C₁₋₄alkyl and—CH₂-cyclopropyl.
 5. A compound according to claim 4 wherein R² ishydrogen.
 6. A compound according to claim 1 wherein R⁶ is C₁₋₄alkyl. 7.A compound according to claim 1 wherein m is selected from 0, 1 and 2.8. A process for preparing a compound as claimed in claim 1 whichcomprises: reacting a compound of formula (XVI)

wherein R³, U, X, Y and r are as defined in claim 1, with a compound offormula (XVII)R¹ (CH₂)_(m)NH₂  (XVII) wherein R¹ and m are as defined in claim 1,under amide forming conditions, followed by reaction with a compound offormula (XVIII)R²-hal  (XVIII) in which R² is as defined in claim 1 and hal is halogen,in the presence of a base.
 9. A pharmaceutical composition comprising acompound according to claim 1 or a pharmaceutically acceptable salt orsolvate thereof, in admixture with one or more pharmaceuticallyacceptable carriers, diluents or excipients.
 10. A compound according toclaim 1 which is:N-(3-Hydroxypropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(Cyclopropyl)-2′-methyl-5′-(5-methyl-,1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-[(Dimethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(Cyclopropyimethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-[3-(Diethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(Cyclopropylmethyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(3-Hydroxpropyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-Cyclohexyl-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-Dicyclopropylmethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-pentyl-1,1′-biphenyl-4-carboxamide;N-(Cyclopropylmethyl)-5′-(5-ethyl-1,3,4-oxadiazol-2-yl)-2′-methyl-1,1′-biphenyl-4-carboxamide;N-(Cyclopropylmethyl)-2′-methyl-5′-(5-n-propyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-[2-(3,4-Dimethoxyphenylamino)-2-oxoethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(3,3-Dimethylbutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(2,3-Dimethylcyclohexyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(Isobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-[2,2-Dimethyl-1-(methylaminocarbonyl)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;2′-Methyl-N-(3-methylcyclohexyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-Cyclohexyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-Cyclopropyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;(1,2-Dimethylpropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(1,3-Dimethylpentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(2-Cyclohexylethyl)-2′-methyl-5′-(5-methyl-,1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;2′-Methyl-N-(2-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(Cyclobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(1-Cyclopropylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;N-(2,4-Dimethyl-3-pentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;2′-Methyl-N-(1-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;or and2′-Methyl-N-(2-methylallyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.
 11. A compoundaccording to claim 6 wherein R⁶ is methyl.
 12. A compound according toclaim 1 wherein R⁶ is methyl; R² is hydrogen or methyl, X and Y arehydrogen, and r is
 0. 13. A compound according to claim 12 wherein R¹ ishydroxy, cyclopropyl, dimethylamine, diethylamine, or CONR⁴R⁵.
 14. Apharmaceutical composition comprising a compound according to claim 10or a pharmaceutically acceptable salt or solvate thereof, in admixturewith one or more pharmaceutically acceptable carriers, diluents orexcipients.